Multiple epidemiological studies have shown associations
between obesity and increased risk for various cancers,1,2 but the
mechanisms underlying the interplay of the two conditions have been poorly
understood. New research from Japan suggests obesity-induced changes in the gut
microbiome could be one potential culprit,3 providing new directions to develop
microbiome-targeted diagnostics and interventions.

A
team led by Eiji Hara, chief of the Division of Cancer Biology at the Japanese Foundation for Cancer Research, has traced the
association between obesity and increased cancer risk to gut microbiota
communities that produce a DNA-damaging bile acid. The work also elucidates the
role of cellular senescence in cancer, something Hara has been studying for the
past decade.

Senescence
typically is viewed as a tumor-suppressive mechanism, but recent studies by
Hara and others have found that senescent cells can take on a secretory phenotype
and produce and release inflammatory factors as well as growth factors.4-6

Some
of the factors secreted by these senescent cells have been associated with
increased cancer risk in obesity. Hara's group sought to determine whether
cells that take on the senescence-associated secretory phenotype could be an
underlying contributor to the increased cancer risk in obesity.

To
map out a mechanistic pathway linking obesity to cancer, the researchers
carried out a series of studies in mice exposed to a carcinogen that rendered
them prone to developing hepatocellular carcinoma (HCC) when obese but not when
lean. The obese mice showed increased numbers of hepatic stellate cells with
the senescence-associated secretory phenotype and had higher levels of deoxycholic acid, a bile acid
produced by certain microbial strains in the gut.

Based
on their findings, the researchers hypothesized that obesity can increase the
production of deoxycholic acid in select populations of gut bacteria, which in
turn increases the appearance of senescent hepatic stellate cells that secrete
inflammatory factors and drive the development of HCC (see"Model for obesity-associated liver cancer
driven by the gut microbiome").

Alterations
in gut microbiota have been associated with cancer,7 inflammation8
and obesity.9 The bile acid deoxycholic acid is a metabolite
produced by some strains of bacteria in the gut. The acid causes DNA damage10
and enhances liver carcinogenesis.11

Last
year, researchers at Columbia University published data
suggesting gut microbiota and signaling through toll-like receptors can drive
inflammatory and fibrogenic responses that contribute to carcinogenesis in the
liver.12

"The
importance of the current study is that it gives us an understanding of how
these three seemingly disparate phenomena are mechanistically linked with one
another," said Judith Campisi, a professor at the Buck Institute and a senior scientist at the Lawrence Berkeley National Laboratory. "My
suspicion, though, is that this will be one of multiple mechanisms that can
drive obesity-associated cancers."

Campisi
noted that there could be other bile acids that drive obesity-associated
cancers as well.

"The current study helps set the stage for identifying
the types of bugs and metabolites that could be important to obesity-associated
HCC," said Peter DiStefano, SVP of R&D at Second Genome Inc. "However,
the researchers will need to go beyond enumeration and on to characterizing the
functional role of these bugs and metabolites in the context of the disease."

Second
Genome is developing therapies that can alter the composition and activity of
microbial communities in the body. In June, the company partnered with Johnson & Johnson's Janssen Biotech
Inc. unit to characterize the role of bacterial populations in the human gut in
ulcerative colitis (UC) and identify potential drug targets.

Exploring
opportunities

Hara said his group is planning studies to
determine whether the results in the mouse model will translate into humans.

Such
studies, he said, would include collecting clinical samples and using them to
determine whether levels of deoxycholic acid or deoxycholic acid-producing
bacteria are higher in obese individuals than in nonobese individuals.

"If
our mouse findings translate into humans, one can imagine the possibility of
developing methods to predict obesity-associated cancer risk in the general
population, for example, by measuring the levels of deoxycholic acid or
deoxycholic acid-producing bacteria in fecal samples," Hara told SciBX.
He expects the group still is three to four years away from developing such a
method.

Campisi
said the findings provide general ideas on potential therapeutic and
interventional strategies but expects the near-term application of Hara's work
is likely to be in the diagnostics space.

"The
first area of opportunity is that we can now think about ways to identify and
treat obese people who are at risk of cancer based on targeting the gut
microbiota," she told SciBX. "A second area one may want to
look for therapeutic opportunities is in identifying and interfering with
enzymes that mediate the production of deoxycholic acid or other bile acids
that could increase cancer risk. A third area of opportunity is in identifying
and evaluating compounds that specifically target senescent cells."

Campisi
wanted to see studies that identify additional gut microbiome-derived
metabolites that are able to induce cellular senescence and what distal tissues
they might affect.

DiStefano
agreed that it is still too early to pursue specific therapeutic strategies
based on the reported findings, but he did note that Hara's work supports the
notion that potential targets for diseases in host tissues could reside in
microbes.

In
addition to determining whether the described mechanism in mice will translate
into human systems, DiStefano said it will be important to identify bacterial
strains that can alter the amount of deoxycholic acid and to investigate how
altering levels of the metabolite will affect the phenotype in HCC and other
disease settings.

The
Japanese Foundation for Cancer Research has filed a patent covering the reported
findings. The work is available for licensing and collaboration. Hara said his
group is specifically interested in collaborating with others to develop
methods to prevent the growth of bacteria that produce deoxycholic acid and
strategies to identify high-risk individuals based on measuring deoxycholic
acid levels.

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